Reference Detail

Ref Type

Journal Article

PMID

(29051322)

Authors

Yam C, Xu X, Davies MA, Gimotty PA, Morrissette JJD, Tetzlaff MT, Wani KM, Liu S, Deng W, Buckley M, Zhao J, Amaravadi RK, Haas NB, Kudchadkar RR, Pavlick AC, Sosman JA, Tawbi H, Walker L, Schuchter LM, Karakousis GC, Gangadhar TC

Title

A Multicenter Phase I Study Evaluating Dual PI3K and BRAF Inhibition with PX-866 and Vemurafenib in Patients with Advanced BRAF V600-Mutant Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	1	2018 Jan 01	22-32	Clin Cancer Res

URL

Abstract Text

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination.Experimental Design: We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600-mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment.Results: Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic PTEN mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8+ T-cell infiltration following treatment with PX-866.Conclusions: PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8+ T-cell infiltration in some patients. Clin Cancer Res; 24(1); 22-32. ©2017 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E/K PTEN loss	Advanced Solid Tumor	predicted - sensitive	PX-866 + Vemurafenib	Phase I	Actionable	In a Phase I trial, the combination therapy of PX-866 and Zelboraf (vemurafenib) demonstrated safety and resulted in an objective response in 28% (5/18) of advanced solid tumor patients harboring BRAF V600E or K, and of those five patients, 80% (4/5) also demonstrated loss of PTEN (PMID: 29051322).	29051322